tbuckley/cabot-search huggingface dataset:
TBIO-07. Pediatric tumor classification through genome-wide methylation profiling of extracellular vesicle DNA
Authors: Franz Ricklefs, Cecile Maire, Krys Fita, Friederike Fritzsche, Gertrud Kammler, Manfred Westphal, Katrin Lamszus, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Genome-wide methylation profiling reliably classifies pediatric central nervous system (CNS) tumors. Extracellular vesicles (EVs) are released by pediatric CNS tumor cells (pCC) and contain high molecular weight tumor DNA, rendering EVs a potential biomarker source to identify tumor subgroups, stratify patients and monitor therapy by liquid biopsy. We investigated, whether the DNA in pCC-derived EVs reflects genome-wide tumor methylation profiles and allows tumor subtype classification. Currently, the tests are being expanded to include blood samples (n=80 patients). METHODS: DNA was isolated from EVs secreted by pediatric CNS tumor cells (pCC) as well as from the shortly cultured tumor cells and from the original tumor samples (n=4 patients). Pediatric Fibroblasts and EVs derived thereof were used as a non-tumorous control. EVs were classified by nanoparticle analysis (NTA), immunoblotting, imaging flow cytometry (IFCM and electron microscopy. Genome-wide DNA methylation profiling was performed using an 850k Illumina EPIC array and results were classified according to the DKFZ brain tumor classifier and further analysed by t-SNE and Copy number alteration analysis (CNA). RESULTS: The size range of pCC-derived EVs was 120-150 nm, as measured by NTA. The majority of secreted EVs exhibited high expression of common EV markers (i.e. CD9, CD63 and CD81), as characterized by IFCM. Genome-wide DNA methylation profiling of pCC-derived EVs correctly identified the methylation class of the original tumor (i.e. pilocytic astrocytoma, medulloblastoma). In addition, t-SNE analysis and copy number alterations matched the pattern of the parental pCC and original tumor samples. CONCLUSION: EV DNA faithfully reflects the tumor methylation class and copy number alterations present in the parental cells and the original tumor. Methylation profiling of circulating tumor EV DNA could become a useful tool to detect and classify pediatric CNS tumors.
A phase 2 trial of sintilimab (IBI 308) in combination with CAPEOX and bevacizumab (BBCAPX) as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
Authors: Xuefeng Fang, Chenhan Zhong, Ning Zhu, Shanshan Weng, Hanguang Hu, Jian Wang, Qian Xiao, Jianwei Wang, Yongmao Song, Lifeng Sun, Dong Xu, Xiujun Liao, Caixia Dong, Suzhan Zhang, Jun Li, Ke-Feng Ding, Ying Yuan
Journal: Journal of Clinical Oncology (2022)

3563 Background: The prognosis of metastatic colorectal cancer (mCRC) patients with RAS gene mutation and microsatellite stable (MSS) is poor. MSS patients account for 95% of CRC and have a low response rate to immunotherapy. Previous studies have reported that chemotherapy and anti-angiogenesis therapy can promote immunotherapy response. This study aims to assess the safety and antitumor activity of sintilimab (IBI308) combined with CapeOx and bevacizumab in the first-line treatment of patients with RAS-mutant and MSS mCRC. Methods: This is an open-label, single-arm, phase II trial. Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m 2 , day 1) and capecitabine (1g/m 2 , bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) evaluated via RECIST 1.1 criteria and adverse events according to CTCAE 5.0. Secondary endpoint was progression-free survival (PFS). Results: 25 patients were enrolled and received at least two cycle treatment. At baseline, median age was 60 years (range 45-74), 72% of patients were male, ECOG PS 0/1 was 100%, 60% had liver metastases (mets), and the primary tumor site was right-sided colon in 36.0% and left-side colorectum in 64.0%. 25 patients completed at least one efficacy evaluation. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease (SD). Patients with liver or lung mets had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). Disease control rate (DCR) reached 100%. Median PFS has not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were anemia (19/25, 76.0%), peripheral neurotoxicity (6/25, 24.0%) and neutropenia (17/25, 68.0%). The most frequent grade 3/4 TRAEs were neutropenia (3/25, 12.0%), elevated aspartate transaminase (1/25, 4.0%), elevated alanine transaminase (1/25, 4.0%) and elevated bilirubin (1/25, 4.0%). Conclusions: Combination treatment with sintilimab (IBI308) plus CapeOx and bevacizumab demonstrated a high ORR (84.0%; 93.3% in patients with liver mets, and 100% in patients with lung mets) and a manageable safety profile in RAS-mutant and MSS mCRC. Clinical trial information: NCT05171660. [Table: see text]
A novel microbial-derived peptide therapeutic vaccine (EO2463) as monotherapy and in combination with lenalidomide and rituximab, for treatment of patients with indolent non-Hodgkin lymphoma (SIDNEY).
Authors: Pier Luigi Zinzani, Stephen M. Ansell, Francesc Bosch, Jonathan W. Friedberg, Jean pierre Marolleau, Luca Arcaini, Ramón Garcia-Sanz, Ajay K. Gopal, Carlos Grande, Reid Merryman, Antonio Pinto, Stephen D. Smith, Jose Caetano Villasboas, Danielle Wallace, Jan Fagerberg, Joao Magalhaes, Philippe Armand
Journal: Journal of Clinical Oncology (2022)

TPS7586 Background: EO2463 is a therapeutic vaccine designed to activate existing commensal bacteria-specific memory T cells that cross-react with B cell markers in order to drive anti-tumor immune activity against B-cell malignancies. The four microbial-derived, synthetically produced peptides contained in EO2463 (OMP72, OMP64, OMP65, and OMP66), correspond to cytotoxic CD8 T cell HLA-A2 restricted epitopes, and exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), respectively. In pre-clinical models, these peptides can generate strong immune responses and specifically stimulate cross-reactive cytotoxic CD8 T cells to recognize the chosen B cell targets. EO2463 also contains a CD4 helper peptide referred to as universal cancer peptide 2, derived from the human telomerase reverse transcriptase catalytic subunit. The present study is a first-in-human clinical trial of this microbiome-derived peptide therapeutic cancer vaccine approach in patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: This four-cohort phase 1/2 trial will investigate EO2463 monotherapy, and combinations of EO2463/lenalidomide (EL), EO2463/rituximab (ER), and EO2463/lenalidomide/rituximab (ER 2 ), for treatment of patients with FL and MZL. Cohort 1 is a safety lead-in dose-finding in patients with relapsed/refractory (RR) disease, with a 3-by-3 design to establish the recommended phase 2 dose (RP2D) for EO2463 monotherapy and to confirm the safety of the RP2D for combination schedules of EL, and ER 2 . After the recommended EO2463 monotherapy dose is established, cohorts 2, 3, and 4 will open to accrual. Cohort 2 will investigate EO2463 monotherapy in patients with newly diagnosed FL/MZL who are not in need of treatment; cohort 3 will investigate EO2463 monotherapy, followed by ER in patients with limited tumor burden who need treatment, and cohort 4 will further investigate EL, followed by ER 2 in the RR setting. EO2463 will be administered SC 4 times at 2-week intervals, followed by continued booster administrations every 4 weeks for 9 (Cohorts 2 and 3) or 12 (Cohorts 1 and 4) months. Inclusion/exclusion criteria, and the design and schedule of the intense immune and safety monitoring will be presented. The safety lead-in dose-finding is currently ongoing, and no safety concerns have been observed thus far. Clinical trial information: NCT04669171.
ETMR-16. Embryonal tumors with multi-layered rosettes: A case series in treatment for newly diagnosed children
Authors: Hung Tran, Ashley Margol, Jennifer Cotter, Linda Szymanski, Katrina O’Halloran, Benita Tamrazi, George Michaiel, Eisha Christian, Darian Esfahani, Tom Belle Davidson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Embryonal tumors with multi-layered rosettes (ETMRs) are rare pediatric brain tumors with poorly defined prognostic features, standard of care treatments or outcome data. Recent data suggest that high-dose chemotherapy and radiotherapy is correlated with improved survival compared to chemotherapy alone. CASE DESCRIPTIONS: Four patients with newly diagnosed ETMRs were treated with 2 cycles of induction chemotherapy per PBTC-026 using isotretinoin, vorinostat, vincristine, cisplatin, etoposide, cyclophosphamide with added intrathecal topotecan. Second look surgery was performed if not in complete remission (CR). Consolidation was with three cycles of marrow-ablative chemotherapy (carboplatin and thiotepa) with autologous hematopoietic cell rescue followed by focal irradiation and 12 cycles of maintenance chemotherapy with intrathecal topotecan, vorinostat and isotretinoin. Patient 1 was a 3-year-old female with right parietal tumor, localized, and achieved gross total resection (GTR). Patient 2 was an 11-month-old male with posterior fossa tumor, localized, and achieved subtotal resection. Patient 3 was a 9-month-old female with posterior fossa tumor with near GTR, and metastasis to T12/L1 and L3/L4. [DTB1] [HNT2] Patient 4 was a 34-month-old male with a right frontal lobe tumor, localized and achieved GTR. Patient 1 is now 18 months from diagnosis and in CR. Patient 2 had second look surgery both after induction and consolidation but suffered neurologic injury to the brainstem which led family to decline further therapy. He is currently 14 months from diagnosis with stable residual disease. Patient 3 had local disease recurrence following radiation therapy at 10 months post diagnosis[DTB3] [HNT4] , prior to maintenance. Patient 4 remains in CR at 13 months from diagnosis, currently in maintenance with vorinostat and isotretinoin but declined intrathecal topotecan. CONCLUSION: This case series adds to current knowledge of intensive multi-modal therapy for newly diagnosed ETMR. Further study to define standard optimal treatments in this high-risk group of patients is warranted.
Association of fatty liver index with all-cause and disease-specific mortality: A nationwide cohort study
Authors: Goh Eun Chung, Su-Min Jeong, Eun Ju Cho, Jeong-Ju Yoo, Yuri Cho, Kyu Na Lee, Dong Wook Shin, Yoon Jun Kim, Jung-Hwan Yoon, Kyungdo Han, Su Jong Yu
Journal: Metabolism (2022)
Targeting BACE1 to restore functional angiogenesis in type 2 diabetes
Authors: E Clavane, RM Cubbon, V Caolo, PJ Meakin
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation British Microcirculation and Vascular Biology Society Background β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease notorious for its contribution to amyloid plaque formation in the pathophysiology of Alzheimer’s disease (AD) [1]. Further research has suggested a role for BACE1 in vascular homeostasis [2,3] and has shown that it proteolytically cleaves various angiogenic signalling factors including VEGF receptor 1 (VEGFR1) [2], NOTCH ligands [4] and the insulin receptor [5]. Similar to AD, BACE1 activity is elevated in models of type 2 diabetes [5], suggesting a potential role for its contribution to aberrant vessel growth characteristic of diabetes-related complications. Purpose Type 2 diabetes dramatically increases an individual's risk of developing microvascular complications and consequent lower limb amputations [6]. Therefore, identifying novel roles for BACE1 in angiogenic dysregulation will aid progression of future biomedical interventions in this field. Methods Retinal staining and the fibrin gel angiogenesis assay were used to identify a role for BACE1 in vessel growth in vivo and in vitro, respectively. Endothelium of the developing retinal vasculature in BACE1-/- and wild type (WT) mice was stained with IsolectinB4-Alexa488 and imaged using confocal microscopy. Sprout formation was further analysed using the fibrin gel angiogenesis assay with human umbilical vein endothelial cells (HUVECs) treated with or without a highly specific BACE1 inhibitor or transfected to over-express BACE1. Primary isolated pulmonary endothelial cells (PECs) were isolated from BACE1-/- and wild type control mice prior to Western blots, and real-time PCR. Results BACE1-/- retinas had increased branch points, vasculature area and quantity of filopodia compared to WT mice. Moreover, BACE1-/- PECs had reduced NOTCH1 signalling (26.73% ± 14.15, P=0.05) and soluble Jagged-1 protein (28.48% ± 14.61, P=&amp;lt;0.05). HUVECs treated with a BACE1 inhibitor had increased sprouting (18.70%± 5.92, P=&amp;lt;0.05) as well as increased phosphorylation of eNOS (83% ± 22, P=&amp;lt;0.05) and Akt (85.5% ± 9.24, P=NS) compared to untreated cells. Moreover, HUVECs transfected to over-express BACE1 had decreased sprouting (35.22% ± 7.34, P=&amp;lt;0.01) and increased NOTCH1 signalling (23.4% ± 2.42, P=0.01). Conclusion Our findings indicate a role of BACE1 in negatively regulating angiogenesis, possibly via NOTCH1 or Akt/eNOS/NO signalling. This provides a potential therapeutic purpose for BACE1 inhibitors, previously trialled to treat AD, in normalising BACE1 levels in individuals with type 2 diabetes and preventing associated microvascular complications.
EPEN-12. Sunitinib induces apoptosis-mediated cytotoxicity in PFA ependymoma
Authors: Bohdan O'Shaughnessy, Andrew Donson, Vladimir Amani, Andrea Griesinger, Enrique Grimaldo, Faith Harris, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract Ependymoma (EPN) has been previously shown to be selectively targeted by three classes of FDA-approved chemotherapy drugs: fluorinated pyrimidines, retinoids, and a subset of small molecule receptor tyrosine kinase inhibitors (RTKIs). We have identified sunitinib malate as an RTKI with ependymoma selectivity, in addition to previously identified ependymoma-selective RTKIs axitinib, imatinib, and pazopanib. Sunitinib—which targets VEGFR, PDGFR and c-kit—elicited unexpectedly high levels of cytotoxic apoptosis (caspase 3/7 cleavage) in EPN PFA cell lines harboring high-risk chromosome 1q gain and 6q loss. In this in-vitro screen of 100+ FDA-approved chemotherapy drugs, sunitinib was the only RTKI in the top five most cytotoxic drugs, a group that included idarubicin HCl, topotecan HCl, daunorubicin HCl, and doxorubicin. Additionally, sunitinib exhibited comparable caspase 3/7 cleavage levels in normoxia and hypoxia, suggesting that this therapy would be as effective in treatment of tumors with potentially resistant hypoxic necrotic cores. The effect of sunitinib on EPN cellular proliferation was tracked visually using Incucyte cell imaging technology, demonstrating consistent dose-dependent inhibition of proliferation. Sunitinib achieved more acute upregulation of apoptosis than axitinib, an EPN-selective RTKI currently being studied in preclinical models. A prior phase II trial of sunitinib in pediatric EPN and high-grade glioma showed that treatment was well tolerated but with no clinical benefit as a monotherapy. However, given encouraging clinical results of combining sunitinib with radiation, our ongoing preclinical studies of sunitinib in EPN are being conducted in the context of radiation which is standard treatment for EPN. Sunitinib presents a promising treatment to an intractable pediatric brain tumor that exhibits high rates of relapse and morbidity in affected individuals.
The correlation of homologous recombination deficiency status with and Olaparib efficacy in Chinese ovarian cancer patients.
Authors: Yongpai Peng, Qingsheng Xie, Guocai Xu, Bingzhong Zhang
Journal: Journal of Clinical Oncology (2022)

e17556 Background: Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2, results in homologous recombination deficiency (HRD) can be a target for therapeutic strategies of ovarian cancer (OC) including poly (ADP-ribose) polymerase inhibitors (PARPi). Here, we proposed an emerging method based on ADx-GSS algorithm to predict HRD status and explore the correlation between HRD status and first-line maintenance therapy of Olaparib in OC patients or Olaparib maintenance therapy in platinum-sensitive relapsed (PSR) OC patients. Methods: Formalin-fixed, paraffin-embedded tissues of 38 consented OC patients between January 2016 and March 2021 were retrospectively collected. Genomic DNA was extracted and subjected to AmoyDx HRD Focus Panel (Amoy Diagnostics Co., Ltd) covering HRD score and BRCA1/2. The HRD score was calculated as the weighted sum of different types of copy number variation (CNV) trained through BRCAness events. Tumors were defined as genomic instability with an HRD score of ≥ 50 (i.e. HRD-positive). The primary endpoint was progression-free survival (PFS), and was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: Histology of collected samples were mostly serous OC (84.2%). All samples were at stage III-IV (80.84%). The fractions of HRD-positive (n = 26) and HRD-negative (n = 12) group were 68.4%, and 31.6%, respectively. 65.8% (n = 25) of the OC patients had received Olaparib first-line maintenance therapy and 34.2% (n = 13) of PSR patients had received Olaparib maintenance therapy. In December 2021, 34.2% (n = 13) of the whole patients had relapsed. A significant PFS benefit was seen in HRD-positive patients compared with HRD-negative ones (P = 0.0017) or in the first-line maintenance treated population (P = 0.0068). In patients with HRD-positive tumors that did not have BRCA mutations, the PFS benefit was improved versus HRD-negative patients without BRCA mutations. However, Olaparib showed no efficacy difference between HRD-positive and HRD-negative tumor in PSR OC patients. Conclusions: HRD status tested by AmoyDx HRD Focus Panel is significantly correlated with the efficacy of Olaparib, and our results demonstrated a significant PFS benefit for HRD-positive patients compared with HRD-negative patients, especially for patients received Olaparib first-line maintenance therapy.
Can pelvic lymph node dissection be omitted at the time of radical prostatectomy in patients with a negative preoperative 68Ga-PSMA PET/CT? The importance of patient risk stratification according to individual risk of lymph node metastases
Authors: E. Mazzone, D. Robesti, G. Gandaglia, A. Stabile, V. Cucchiara, C.A. Bravi, A. Necchi, D. Raggi, L. Marandino, G.O. Cirulli, E. Balestrazzi, S. Fanti, V. Cucchiara, A. Farolfi, L. Bianchi, R. Schiavina, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Regular Use of Erectile Dysfunction Drugs Associated With Eye Problems
Authors: Anita Slomski
Journal: JAMA (2022)

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A bioequivalence study of a novel liquid and ready-to-use temozolomide oral suspension and temozolomide capsules in patients with primary tumors central nervous system malignancies.
Authors: Francois Ducray, Carole Ramirez, Marie Robert, Fontanilles Maxime, Charlotte Bronnimann, Olivier L. Chinot, Florian Estrade, Xavier Durando, Jeremy Bastid, Hugues Bienaymé, Caroline Lemarchand
Journal: Journal of Clinical Oncology (2022)

e22008 Background: Oral temozolomide capsule is approved for the treatment of glioma and malignant glioblastoma in adults and in Europe in children over 3-years. As recommended by international pediatric medical associations, temozolomide is also used for the treatment of high-risk relapsed or refractory neuroblastoma, a solid tumor affecting young children. Nevertheless, capsules are not adapted to the pediatric population leading caregivers to handle temozolomide capsules, which bears major risks (i.e. dose inaccuracy, temozolomide instability and exposure to cytotoxic drug). To overcome this situation, a temozolomide oral suspension (Kimozo) was developed. The aim of this phase I study was to demonstrate bioequivalence between the temozolomide oral suspension and the temozolomide capsules (Temodal) and to assess the general and local safety in adult patients. Methods: A randomized, open-label, two-way crossover, single-dose bioequivalence study was performed in 8 centers. Adult patients with primary malignancies and treated with temozolomide 200 mg/m² as monotherapy received a single oral administration of the oral suspension (test) or capsule (reference) on days 1 and 2 of a 5-day cycle, depending on the randomization, and under fasting conditions. Fourteen blood samples were collected over 10-hr in each period for pharmacokinetic purpose. General and buccal safety was assessed along the study. The assessment of bioequivalence was based upon 90% confidence intervals (CI) for the ratio of the population geometric means (test/reference) for maximum plasma concentration (C max ) and area under the curve (AUC 0-t ). Results: Among the thirty-six patients enrolled in the study, thirty were assessable for pharmacokinetic primary endpoint. The point estimate and the 90% CI of the ratios of C max and AUC 0-t were 107.62 (98.07-118.09) and 97.18 (95.05-99.35), respectively. The results obtained satisfy the bioequivalence criteria of the Bioequivalence Guidelines (90% CI between 80.00% and 125.00%). Neither serious adverse events nor adverse events of special interest (i.e. mucositis) were reported. Conclusions: The oral suspension of temozolomide (Kimozo) and capsule of temozolomide (Temodal) are bioequivalent under fasting conditions in patients with CNS primary malignancies, supporting that they are therapeutic equivalent. Clinical trial information: NCT04467346.